NM_001292063.2:c.4238G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_001292063.2(OTOG):c.4238G>A(p.Arg1413Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000466 in 1,546,540 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00026 ( 1 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.12

Publications

0 publications found

Variant links:

Genes affected

OTOG (HGNC:8516): (otogelin) The protein encoded by this gene is a component of the acellular membranes of the inner ear. Disruption of the orthologous mouse gene shows that it plays a role in auditory and vestibular functions. It is involved in fibrillar network organization, the anchoring of otoconial membranes and cupulae to the neuroepithelia, and likely in sound stimulation resistance. Mutations in this gene cause autosomal recessive nonsyndromic deafness, type 18B. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

OTOG Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 18B
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

OTOG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008218646).

BP6

Variant 11-17608377-G-A is Benign according to our data. Variant chr11-17608377-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 504783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00237 (361/152346) while in subpopulation AFR AF = 0.00827 (344/41584). AF 95% confidence interval is 0.00755. There are 0 homozygotes in GnomAd4. There are 167 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.4238G>A	p.Arg1413Gln	missense_variant	Exon 34 of 56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.4274G>A	p.Arg1425Gln	missense_variant	Exon 33 of 55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOG	ENST00000399397.6 link	c.4238G>A	p.Arg1413Gln	missense_variant	Exon 34 of 56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 link	c.4274G>A	p.Arg1425Gln	missense_variant	Exon 33 of 55	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000342528.2 link	n.1576G>A		non_coding_transcript_exon_variant	Exon 10 of 22	2

Frequencies

GnomAD3 genomes

AF:

0.00237

AC:

361

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00830

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000508

AC:

AN:

143590

AF XY:

0.000388

show subpopulations

Gnomad AFR exome

AF:

0.00864

Gnomad AMR exome

AF:

0.000558

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000187

Gnomad OTH exome

AF:

0.000244

GnomAD4 exome

AF:

0.000257

AC:

359

AN:

1394194

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

148

AN XY:

687456

show subpopulations

African (AFR)

AF:

0.00881

AC:

277

AN:

31438

American (AMR)

AF:

0.000570

AC:

AN:

35118

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25090

East Asian (EAS)

AF:

0.00

AC:

AN:

35492

South Asian (SAS)

AF:

0.0000511

AC:

AN:

78254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47876

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.0000223

AC:

AN:

1077410

Other (OTH)

AF:

0.000570

AC:

AN:

57850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00237

AC:

361

AN:

152346

Hom.:

Cov.:

AF XY:

0.00224

AC XY:

167

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00827

AC:

344

AN:

41584

American (AMR)

AF:

0.000849

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00108

Hom.:

Bravo

AF:

0.00274

ExAC

AF:

0.000546

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Sep 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 14, 2018

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arg1425Gln in exon 33 of OTOG: This variant is not expected to have clinical sig nificance because it has been identified in 1.0% (5/492) of African chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov /projects/SNP; dbSNP rs143848095). -

Autosomal recessive nonsyndromic hearing loss 18B

Benign:1

Jul 28, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.036

T;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

D;D

MetaRNN

Benign

0.0082

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.8

M;.

PhyloP100

4.1

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.64

N;.

REVEL

Benign

0.082

Sift

Benign

0.061

T;.

Sift4G

Uncertain

0.032

D;D

Vest4

0.21

MVP

0.33

ClinPred

0.041

GERP RS

3.4

Varity_R

0.078

gMVP

0.56

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over